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Abstract:

This invention relates to novel 4-dimethylaminobutyric acid derivatives
of the formula
##STR00001##
wherein A1, A2, R1, m and n are as defined in the
description and in the claims, as well as pharmaceutically acceptable
salts thereof. These compounds inhibit carnitine palmitoyl transferase
(CPT) activity, in particular CPT2 activity, and can be used as
medicaments in methods for the treatment of diseases modulated by CPT2
inhibitors.

Claims:

1. A compound of the formula ##STR00030## wherein A1 is a bond,
A2 is selected from the group consisting of a bond, O,
O(CH2)2O, S, SO2, CF2 and NR2, wherein R2
is hydrogen or lower alkyl, m is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10
and 11, n is selected from 0, 1, 2, 3, 4 and 5, R1 is aryl selected
from phenyl and naphthyl, said aryl being unsubstituted or substituted by
one, two, three, four or five groups selected from the group consisting
of lower alkyl, halogen, lower halogenalkyl, lower alkoxy and phenyl, or
heteroaryl selected from the group consisting of pyridyl, thienyl and
thiazolyl, said heteroaryl being unsubstituted or substituted by one, two
or three groups selected from lower alkyl, halogen, lower halogenalkyl,
lower alkoxy and phenyl, and pharmaceutically acceptable salts thereof.

3. The compound of formula I according to claim 1, wherein A2 is
selected from the group consisting of a bond, O, O(CH2)2O, S,
SO2 and NR2, wherein R2 is hydrogen or lower alkyl.

4. The compound of formula I according to claim 3, wherein A2 is
selected from the group consisting of a bond, O and O(CH2)2O.

5. The compound of formula I according to claim 4, wherein A2 is O
or O(CH2)2O.

6. The compound of formula I according to claim 4, wherein A2 is a
bond.

7. The compound of formula I according to claim 1, wherein m is selected
from 6, 7, 8, 9, and 11.

8. The compound of formula I according to claim 1, wherein n is selected
from 0, 1, 2 and 3.

9. The compound of formula I according to claim 8, wherein n is selected
from 0 or 1.

10. The compound of formula I according to claim 1, wherein R1 is
aryl selected from phenyl and naphthyl, said aryl being unsubstituted or
substituted by one, two, three, four or five groups selected from the
group consisting of lower alkyl, halogen, lower halogenalkyl, lower
alkoxy and phenyl.

11. The compounds of formula I according to claim 10, wherein R1 is
phenyl substituted by one, two, three, four or five groups selected from
the group consisting of lower alkyl, halogen, lower halogenalkyl, lower
alkoxy and phenyl, provided that at least one of the substituents is
halogen or lower halogenalkyl.

12. The compound of formula I according to claim 1, wherein R1 is
heteroaryl selected from the group consisting of pyridyl, thienyl and
thiazolyl, said heteroaryl being unsubstituted or substituted by one, two
or three groups selected from lower alkyl, halogen, lower halogenalkyl,
lower alkoxy and phenyl.

13. The compound of formula I according to claim 12, wherein R1 is
heteroaryl selected from the group consisting of pyridyl, thienyl and
thiazolyl.

14. A compound of formula I according to claim 1 having the formula
##STR00031##

17. A compound of formula I according to claim 1, which is
(R)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid.

18. A process for the preparation of compounds of formula I as defined in
claim 1, which process comprises a) condensating an amine of formula
##STR00032## wherein RP is methyl, ethyl or benzyl, with a
carboxylic acid of the formula ##STR00033## wherein A1 is a bond
and A2, m, n and R1 are as defined in claim 1, in the presence
of a base and a condensing agent to obtain a compound of the formula
##STR00034## and transforming the compound of formula IV into a compound
of formula I, wherein A1 is a bond, by ester hydrolysis or
hydrogenation.

19. A process for the preparation of compounds of formula I as defined in
claim 1, which process comprises a) condensating the amine of formula
##STR00035## wherein RP is methyl, ethyl or benzyl, with an
isocyanate of the formula
O═C═N--(CH2)m-A2-(CH2)n--R1 V
wherein A2, m, n and R1 are as defined in claim 1, in the
presence of a base to obtain a compound of the formula ##STR00036## and
transforming the compound of formula VI into a compound of formula I,
wherein A1 is NH, by ester hydrolysis or hydrogenation.

20. A process for the preparation of compounds of formula I as defined in
claim 1, which process comprises a) condensating the amine of formula
##STR00037## wherein RP is benzyl, with a carboxylic acid of the
formula ##STR00038## wherein m and R1 are as defined in claim 1,
in the presence of a base and a condensing agent to obtain a compound of
the formula ##STR00039## and transforming the compound of formula VIII
into a compound of formula I, wherein A2 is a bond and n is 2, by
hydrogenation.

21. A pharmaceutical composition comprising a compound of formula I
according to claim 1 and a pharmaceutically acceptable carrier and/or
adjuvant.

22. A method for the treatment of diseases which are modified by CPT2
inhibitors, comprising administering a compound of formula I according to
claim 1 to a human being or animal.

23. A method for the therapeutic treatment of diseases which are
modulated by CPT2 inhibitors, particularly for the therapeutic treatment
of hyperglycemia, glucose tolerance disorders, diabetes and associated
pathologies, non-insulin dependent diabetes mellitus, obesity,
hypertension, insulin resistance syndrome, metabolic syndrome,
hyperlipidemia, hypercholesterolemia, fatty liver disease,
atherosclerosis, congestive heart failure and renal failure, which method
comprises administering a compound of formula I according to claim 1 to a
human being or animal.

24. A method for the therapeutic treatment of hyperglycemia and
non-insulin dependent diabetes mellitus, comprising administering a
compound of formula I according to claim 1 to a human being or animal.

31. A compound of formula I according to claim 1, selected from the group
consisting of
(R)-3-{7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoylamino}-4-dimethylamino-
-butyric acid,
(R)-4-dimethylamino-3-[9-(methyl-phenethyl-amino)-nonanoylamino]-butyric
acid, (R)-4-dimethylamino-3-(9-phenethylamino-nonanoylamino)-butyric
acid, (R)-4-dimethylamino-3-[9-(methyl-phenyl-amino)-nonanoylamino]-butyr-
ic acid, and pharmaceutically acceptable salts thereof.

33. A compound of formula I according to claim 1, selected from the group
consisting of
(R)-4-dimethylamino-3-[10-(4-trifluoromethyl-phenyl)-decanoylamino]-butyr-
ic acid, (R)-3-[10-(2,3-difluoro-phenyl)-decanoylamino]-4-dimethylamino-bu-
tyric acid, (R)-4-dimethylamino-3-(10-thiophen-3-yl-decanoylamino)-butyric
acid, (R)-4-dimethylamino-3-(9-phenethyloxy-nonanoylamino)-butyric acid,
(R)-4-dimethylamino-3-[8-(2-phenoxy-ethoxy)-octanoylamino]-butyric acid,
and pharmaceutically acceptable salts thereof.

Description:

PRIORITY TO RELATED APPLICATION(S)

[0001] This application is a continuation application of U.S. Ser. No.
12/430,934, filed Apr. 28, 2009. This application claims the benefit of
European Patent Application No. 08155323.2, filed Apr. 29, 2008, which is
hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention is concerned with novel 4-dimethylaminobutyric acid
derivatives, a process for the manufacture of these compounds,
pharmaceutical preparations which contain such compounds as well as the
use of these compounds for the production of medicaments.

SUMMARY OF THE INVENTION

[0003] More specifically, the invention relates to compounds of the
formula

##STR00002##

wherein [0004] A1 is NH or a bond, [0005] A2 is selected from
the group consisting of a bond, O, O(CH2)2O, S, SO2,
CF2 and NR2, [0006] wherein R2 is hydrogen or lower alkyl,
[0007] m is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, [0008] n is
selected from 0, 1, 2, 3, 4 and 5, [0009] R1 is aryl selected from
phenyl and naphthyl, said aryl being unsubstituted or substituted by one,
two, three, four or five groups selected from the group consisting of
lower alkyl, halogen, lower halogenalkyl, lower alkoxy and phenyl, or
heteroaryl selected from the group consisting of pyridyl, thienyl and
thiazolyl, said heteroaryl being unsubstituted or substituted by one, two
or three groups selected from lower alkyl, halogen, lower halogenalkyl,
lower alkoxy and phenyl, [0010] and pharmaceutically acceptable salts
thereof.

DETAILED DESCRIPTION

[0011] More specifically, the invention relates to compounds of the
formula

##STR00003##

wherein [0012] A1 is NH or a bond, [0013] A2 is selected from
the group consisting of a bond, O, O(CH2)2O, S, SO2,
CF2 and NR2, [0014] wherein R2 is hydrogen or lower alkyl,
[0015] m is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, [0016] n is
selected from 0, 1, 2, 3, 4 and 5, [0017] R1 is aryl selected from
phenyl and naphthyl, said aryl being unsubstituted or substituted by one,
two, three, four or five groups selected from the group consisting of
lower alkyl, halogen, lower halogenalkyl, lower alkoxy and phenyl, or
[0018] heteroaryl selected from the group consisting of pyridyl, thienyl
and thiazolyl, said heteroaryl being unsubstituted or substituted by one,
two or three groups selected from lower alkyl, halogen, lower
halogenalkyl, lower alkoxy and phenyl, [0019] and pharmaceutically
acceptable salts thereof.

[0020] Elevated plasma levels of free fatty acids (FFAs) cause acute and
long-term peripheral and hepatic insulin resistance. Increased plasma FFA
levels and increase FFA oxidation are associated with type 2 diabetes.
Hyperglycemia after an overnight fast is a major hallmark and an
important diagnostic criterion of diabetes, and excessive gluconeogenesis
is mainly responsible for the postabsorptive hyperglycemia in diabetic
patients. High levels of free fatty acids (FFA) lead to an increase of
liver mitochondrial β-oxidation, which results in increased
concentrations of acetyl CoA. This provides increased energy (ATP) and
reducing force (NADH) for gluconeogenesis. Increased acetyl CoA levels
also stimulate gluconeogenesis by an allosteric activation of pyruvate
carboxylase. Thereby, reduction of excessive liver β-oxidation,
which is crucial to drive efficient gluconeogenesis, should lead to a
reduction of fasting hyperglycemia in diabetic patients. The
mitochondrial oxidation of long-chain FFA requires the intervention of
two membrane-bound carnitine-dependent palmitoyltransferases (CPTs).
CPT1, the outer mitochondrial membrane enzyme, catalyzes the formation of
long-chain acylcarnitines. Liver (L-CPT1) and muscle (M-CPT1) CPT1
isoforms are encoded by two different genes and inhibited by malonyl-CoA.
The N-terminal domain of L-CPT1 confers its lower sensitivity to malonyl
CoA. CPT2, the inner mitochondrial membrane enzyme, reconverts long-chain
acylcarnitines into long-chain acyl CoA esters. Long-chain acyl-CoAs are
then β-oxidized to acetyl-CoA, which activates the pyruvate
carboxylase and gluconeogenesis. According to the mechanism of action
described above, pharmaceutically active substances which inhibit
transport of long chain FFA though the inhibition of CPTs, reduce liver
β-oxidation, consequently inhibit gluconeogenesis and therefore
counteract hyperglycemia.

[0022] The novel compounds of the present invention exceed the compounds
known in the art, inasmuch as they inhibit in particular or
preferentially CPT2 activity. They are therefore expected to have an
enhanced therapeutic potential compared to the compounds already known in
the art.

A. DEFINITIONS

[0023] Unless otherwise indicated, the following definitions are set forth
to illustrate and define the meaning and scope of the various terms used
to describe the invention herein.

[0024] In this specification the term "lower" is used to mean a group
consisting of one to seven, preferably of one to four carbon atom(s).

[0025] The term "halogen" refers to fluorine, chlorine, bromine and
iodine, with fluorine, chlorine and bromine being preferred.

[0026] The term "alkyl", alone or in combination with other groups, refers
to a branched or straight-chain monovalent saturated aliphatic
hydrocarbon radical of one to twenty carbon atoms, preferably one to
sixteen carbon atoms, more preferably one to ten carbon atoms. The term
"C1-10-alkyl" refers to a branched or straight-chain monovalent
saturated aliphatic hydrocarbon radical of one to ten carbon atoms, such
as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl,
pentyl, 1,1,3,3-tetramethyl-butyl and the like. Lower alkyl groups as
described below also are preferred alkyl groups.

[0027] The term "lower alkyl" or "C1-C7-alkyl", alone or in
combination with other groups, refers to a branched or straight-chain
monovalent alkyl radical of one to seven carbon atoms, preferably one to
four carbon atoms. This term is further exemplified by such radicals as
methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the
like.

[0028] The term "lower halogenalkyl" or "halogen-C1-C7-alkyl"
refers to lower alkyl groups as defined above wherein at least one of the
hydrogen atoms of the lower alkyl group is replaced by a halogen atom,
preferably fluoro or chloro, most preferably fluoro. Among the preferred
lower halogenalkyl groups are trifluoromethyl, difluoromethyl,
trifluoroethyl, 2,2-difluoroethyl, fluoromethyl and chloromethyl, with
trifluoromethyl being especially preferred.

[0029] The term "alkoxy" or "lower alkoxy" refers to the group R'--O--,
wherein R' is lower alkyl and the term "lower alkyl" has the previously
given significance. Examples of lower alkoxy groups are e.g. methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and
tert-butoxy, preferably methoxy and ethoxy and most preferred methoxy.

[0030] Compounds of formula (I) can form pharmaceutically acceptable
salts. Compounds of formula (I) can form salts with bases. Examples of
such salts are alkaline, earth-alkaline and ammonium salts such as e.g.
Na--, K--, Ca-- and trimethylammonium salt. Compounds of formula I can
also form pharmaceutically acceptable acid addition salts. Examples of
such pharmaceutically acceptable salts are salts of compounds of formula
(I) with physiologically compatible mineral acids, such as hydrochloric
acid, sulphuric acid or phosphoric acid; or with organic acids, such as
methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid,
citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or
salicylic acid. The term "pharmaceutically acceptable salts" refers to
all these salts.

B. DETAILED DESCRIPTION

[0031] In detail, the present invention relates to compounds of the
formula

##STR00004##

wherein [0032] A1 is NH or a bond, [0033] A2 is selected from
the group consisting of a bond, O, O(CH2)2O, S, SO2,
CF2 and NR2, [0034] wherein R2 is hydrogen or lower alkyl,
[0035] m is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, [0036] n is
selected from 0, 1, 2, 3, 4 and 5, [0037] R1 is aryl selected from
phenyl and naphthyl, said aryl being unsubstituted or substituted by one,
two, three, four or five groups selected from the group consisting of
lower alkyl, halogen, lower halogenalkyl, lower alkoxy and phenyl, or
heteroaryl selected from the group consisting of pyridyl, thienyl and
thiazolyl, said heteroaryl being unsubstituted or substituted by one, two
or three groups selected from lower alkyl, halogen, lower halogenalkyl,
lower alkoxy and phenyl, [0038] and pharmaceutically acceptable salts
thereof.

[0039] Compounds of formula I are individually preferred and
pharmaceutically acceptable salts thereof are individually preferred,
with the compounds of formula I being particularly preferred.

[0040] Preferred are further compounds of formula I according to the
invention, wherein A1 is a bond.

[0041] Furthermore, compounds of formula I according to the present
invention are preferred, wherein A2 is selected from the group
consisting of a bond, O, O(CH2)2O, S, SO2 and NR2,
wherein R2 is hydrogen or lower alkyl.

[0042] More preferably, A2 is selected from the group consisting of a
bond, O and O(CH2)2O.

[0043] A group of more preferred compounds of formula I are those, wherein
A2 is O or O(CH2)2O, with those compounds of formula I
being especially preferred, wherein A2 is O (oxygen).

[0044] Another group of preferred compounds of formula I are those,
wherein A2 is a bond.

[0045] Preferred are further compounds of formula I according to the
present invention, wherein m is selected from 6, 7, 8, 9, 10 and 11.

[0046] Further preferred are compounds of formula I according to the
invention, wherein n is selected from 0, 1, 2 and 3, with those compounds
being more preferred, wherein n is selected from 0 or 1, and those being
most preferred wherein n is 1.

[0047] Especially preferred are compounds of formula I, wherein the sum of
m and n is selected from 8, 9 and 10.

[0048] A group of preferred compounds of formula (I) according to the
invention are further those, wherein R1 is aryl selected from phenyl
and naphthyl, said aryl being unsubstituted or substituted by one, two,
three, four or five groups selected from the group consisting of lower
alkyl, halogen, lower halogenalkyl, lower alkoxy and phenyl.

[0049] Especially preferred are compounds of formula I according to the
invention, wherein R1 is phenyl substituted by one, two, three, four
or five groups selected from the group consisting of lower alkyl,
halogen, lower halogenalkyl, lower alkoxy and phenyl. More preferred are
those compounds of formula I, wherein R1 is phenyl substituted by
one, two, three, four or five groups selected from the group consisting
of lower alkyl, halogen, lower halogenalkyl, lower alkoxy and phenyl
provided that at least one of the substituents is halogen or lower
halogenalkyl. Especially preferred R1 is phenyl substituted by one,
two, three, four or five groups selected from halogen and lower
halogenalkyl.

[0050] Another group of preferred compounds of formula I according to the
present invention are those, wherein R1 is heteroaryl selected from
the group consisting of pyridyl, thienyl and thiazolyl, said heteroaryl
being unsubstituted or substituted by one, two or three groups selected
from lower alkyl, halogen, lower halogenalkyl, lower alkoxy and phenyl.

[0051] Especially preferred are compounds of formula I of the invention,
wherein R1 is heteroaryl selected from the group consisting of
pyridyl, thienyl and thiazolyl.

[0052] Furthermore, compounds of formula I having (R)-configuration are
especially preferred, i.e. these are the compounds having the formula

[0136] Especially preferred is a compound of formula I, which is
(R)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid.

[0137] It will be appreciated that the compounds of general formula I in
this invention may be derivatised at functional groups to provide
derivatives which are capable of conversion back to the parent compound
in vivo.

[0138] The invention also relates to a process for the preparation of
compounds of formula I as defined above, which process comprises

a) condensating an amine of formula

##STR00006##

wherein RP is methyl, ethyl or benzyl, with a carboxylic acid of the
formula

##STR00007##

wherein A1 is a bond and A2, m, n and R1 are as defined
herein before, in the presence of a base and a condensing agent to obtain
a compound of the formula

##STR00008##

and transforming the compound of formula IV into a compound of formula I,
wherein A1 is a bond, by ester hydrolysis or hydrogenation, or b)
condensating the amine of formula

##STR00009##

wherein RP is methyl, ethyl or benzyl, with an isocyanate of the
formula

O═C═N--(CH2)m-A2-(CH2)n--R1 V,

wherein A2, m, n and R1 are as defined herein before, in the
presence of a base to obtain a compound of the formula

##STR00010##

and transforming the compound of formula VI into a compound of formula I,
wherein A1 is NH, by ester hydrolysis or hydrogenation, or c)
condensating the amine of formula

##STR00011##

wherein RP is benzyl, with a carboxylic acid of the formula

##STR00012##

wherein m and R1 are as defined herein before, in the presence of a
base and a condensing agent to obtain a compound of the formula

##STR00013##

and transforming the compound of formula VIII into a compound of formula
I, wherein A2 is a bond and n is 2, by hydrogenation.

[0139] Ester hydrolysis means a base-catalyzed hydrolysis using reagents
such as lithium hydroxide, sodium hydroxide, potassium hydroxide, in
solvents such as water, methanol, ethanol, tetrahydrofuran, or mixtures
thereof, at temperatures between 0° C. and 100° C.
Hydrogenation is normally carried out at a hydrogen pressure of 1 to 10
bar, using a suitable catalyst such as palladium on activated charcoal,
in a solvent such as methanol or ethanol, at a temperature between
0° C. and 50° C., but hydrogenation can also mean reduction
of a double bond using triethysilane and trifluoroacetic acid in an inert
solvent such as toluene or dichloromethane followed by ester hydrolysis
as described hereinbefore.

[0140] As compounds of formula I having (R)-configuration are preferred,
the 3-amino-4-dimethylaminobutyrate of the formula

##STR00014##

is preferably used in the processes of the present invention.

[0141] The present invention also relates to compounds of formula I as
defined above, when prepared by a process as described above.

[0142] In more detail, the compounds of formula I are synthesized from the
corresponding esters 1 (Rp=methyl, ethyl, benzyl), using methods
known in the art. Especially preferred are compounds 1 with
Rp=benzyl, which can be converted to 1 by hydrogenation at a
pressure of 1-10 bar, using a suitable catalyst, e.g., palladium on
activated charcoal, in a solvent such as methanol or ethanol, at 0 to
50° C. Alternatively, esters 1 can be transformed into compounds
of formula I by base-catalyzed hydrolysis, using reagents such as lithium
hydroxide, sodium hydroxide, potassium hydroxide, in solvents such as
water, methanol, ethanol, tetrahydrofuran, or mixtures thereof, at
temperatures between 0° C. and 100° C.

##STR00015##

[0143] Alternatively, compounds of formula I, wherein A2 is a bond
and n is 2, can also be synthesized from ester 2 (in the case where
RP is benzyl) by hydrogenation as described above, whereby a double
bond eventually adjacent to R1 as a result of the synthetic protocol
used (see below) is also reduced. In the case where RP is methyl,
ethyl, or benzyl, the transformation of 2 into a compound of formula I
can also be accomplished in two steps as follows: In a first step the
aforementioned double bond is reduced using triethysilane and
trifluoroacetic acid in an inert solvent such as toluene or
dichloromethane. In the second step the ester group is hydrolyzed, using
reagents such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, in solvents such as water, methanol, ethanol, tetrahydrofuran,
or mixtures thereof, at temperatures between 0° C. and 100°
C.

##STR00016##

[0144] Compounds of formula 1 where A1 is NH can be synthesized from
3-amino-4-dimethylaminobutyrate 3

##STR00017##

and isocyanate 4.

O═C═N--(CH2)m-A-(CH2)n--R1

[0145] The reaction is preferably accomplished in an aprotic solvent such
as dichloromethane or tetrahydrofuran, optionally in the presence of a
base, e.g., triethylamine or 4-methylmorpholine.

[0146] Compounds of formula 1 where A1 is a bond are synthesized from
3-amino-4-dimethylaminobutyrate 3 and carboxylic acid 5.

##STR00018##

[0147] This can be carried out under conditions well known to the person
skilled in the art. Such reactions can conveniently be carried out for
example by mixing carboxylic acid 5 with amine 3 in aprotic solvents such
as dichloromethane, tetrahydrofuran, N,N-dimethylformamide,
N-methylpyrrolidinone and mixtures thereof at temperatures between
0° C. and 60° C. in the presence or absence of a base such
as triethylamine or N,N-diisopropylethylamine, and a condensing agent.
Appropriate condensing agents can be for example
O-(7-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate
(TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluor-
ophophate (HATU), N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate,
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate or others well
known to the person skilled in the art.

[0148] Alternatively, such reactions can be performed in two steps
involving first formation of the acyl halide derivative of 5 and
subsequent coupling reaction with amine 3 in the presence of a base.
Typically employed reagents for the formation of the acyl chloride are
thionyl chloride, phosphorus pentachloride, oxalyl chloride or cyanuric
chloride, and the reaction is generally conducted in the absence of a
solvent or in the presence of an aprotic solvent like dichloromethane,
toluene or acetone. A base can optionally be added, like for example
pyridine, triethylamine, N,N-diisopropylethylamine or 4-methylmorpholine.
The obtained acyl chloride can be isolated or reacted as such with an
amine 3 in an aprotic solvent, like dichloromethane, tetrahydrofuran or
acetone, in the presence of a base. Typical bases are triethylamine,
4-methylmorpholine, pyridine, N,N-diisopropylethyl-amine or
dimethylaminopyridine or mixtures thereof.

[0149] Alternatively, such reactions can be performed in two steps
involving first formation of a mixed anhydride derivative of 5 obtained
by reaction with a reagent such as ethyl chloroformate, isobutyl
chloroformate, or acetic anhydride, and subsequent reaction with amine 3
as described above.

[0150] Compounds of formula 2 are synthesized from
3-amino-4-dimethylaminobutyrate 3 and carboxylic acid 6, in analogy to 1.

##STR00019##

[0151] The synthesis of 3-amino-4-dimethylaminobutyrate 3 is highlighted
in scheme 1 and starts from commercially available N-protected aspartic
acid monoester 7. RP is methyl, ethyl, or benzyl, with benzyl being
especially preferred.

##STR00020##

[0152] In step a, scheme 1, carboxylic acid 7 is reacted with
dimethylamine to the N,N-dimethylamide derivative 8, using reagents and
methods as described for the reaction of carboxylic acid 5 with amine 3.
In step b, scheme 1, N,N-dimethylamide 8 is converted to dimethylamine
derivative 3 by reduction and subsequent removal of the
tert-butoxycarbonyl protective group. Preferred reagents for the
reduction are borane-tetrahydrofuran complex or borane-dimethylsulfide
complex, in an aprotic solvent such as tetrahydrofuran, at temperature
between -20° C. and 80° C. Removal of the
tert-butoxycarbonyl group is accomplished in an acidic environment, using
hydrochloric acid or sulfuric acid, in solvents such as ethanol,
methanol, water or mixtures thereof, at temperatures between 0° C.
and 20° C.

[0153] Isocyanate 4 is synthesized from carboxylic acid 5 as highlighted
in scheme 2. This conversion is accomplished by methods well known in the
art, e.g., Curtius rearrangement. A typical procedure starts the
transformation of 5 to its acyl halide derivative. Typically employed
reagents for the formation of the acyl chloride are thionyl chloride,
phosphorus pentachloride, oxalyl chloride, ethyl chloroformate, isobutyl
chloroformate, or cyanuric chloride, and the reaction is generally
conducted in the absence of a solvent or in the presence of an aprotic
solvent like dichloromethane or toluene. A base can optionally be added,
like for example pyridine, triethylamine, diisopropyl ethyl amine or
4-methylmorpholine. The obtained acyl chloride can be isolated or reacted
as such with sodium azide, leading to the acyl azide derivative of 5,
which is not isolated but heated to >60° C., whereupon it
rearranges to isocyanate 4 under elimination of nitrogen gas.

##STR00021##

[0154] Alternatively, the conversion of 5 to 4 can be accomplished in a
single step, using diphenylphosphoryl azide as azide source, optionally
in the presence of a base, e.g., triethylamine, at temperatures between
0° C. and 110° C., preferably in toluene.

[0155] Carboxylic acids 5 are either commercially available or can be
produced as outlined in schemes 3 to 10.

[0156] When R1 is as described above, A2 is O,
O(CH2)2O, S or SO2, the carboxylic acids 5 can be produced
as described in scheme 3, where X is a leaving group such as bromine,
iodine, or methanesulfonyloxy and PG is an optional protective group,
e.g., tetrahydropyran-2-yl.

##STR00022##

[0157] In step a, scheme 3, compound 10 is alkylated with optionally
protected w-halo or w-sulfonyloxy alcohol 9, leading to 11. The reaction
is performed in a solvent such as ethanol, acetonitrile, or
N,N-dimethylformamide, in the presence of a base, e.g., potassium
carbonate, sodium hydroxide, potassium tert-butylate, or sodium hydride,
at temperatures between 0° C. and 100° C.

[0158] In optional step b (i.e., in the case where PG≠H), the
protective group of 11 is removed, leading to alcohol 12. In the case of
PG=tetrahydropyran-2-yl, this reaction is accomplished using an acid
catalyst such as hydrochloric acid, toluene-4-sulfonic acid, or
pyridinium toluene-4-sulfonate, in a solvent such as water, methanol, or
ethanol, at temperatures between 0° C. and 100° C.

[0159] In step c, scheme 3, alcohol 12 is oxidized to carboxylic acid 5.
Typically employed reagents and conditions for the oxidation of alcohol
12 include pyridinium dichromate, chromium(VI)oxide, or potassium
permanganate. This oxidation of 12 to 5 is also possible for alcohols 12
in which A2 is a bond.

[0160] Alternatively, alcohol 12 can be synthesized as outlined in scheme
4. A2 is oxygen, sulfur, or SO2, R1, m and n are as
defined above. In this route diol 13 and compound 14 are reacted under
Mitsunobu conditions using a phosphine, e.g., triphenylphosphine, and an
azodicarboxylic acid diester, e.g., diethyl azodicarboxylate or
diisopropyl azodicarboxylate, in a solvent such as tetrahydrofuran,
dichloromethane, or toluene, at temperatures between 0° C. and
50° C., leading to 12.

##STR00023##

[0161] Alternatively, alcohol 12 can be synthesized as outlined in scheme
5. In this case A2 is O, S or SO2, R1, m and n are as
defined above and X is a leaving group such as bromine, iodine, or
methanesulfonyloxy. Thus, compound 15 is alkylated with halide or
sulfonate 16. The reaction is performed in a solvent such as ethanol,
acetonitrile, or N,N-dimethylformamide, in the presence of a base, e.g.,
potassium carbonate, sodium hydroxide, potassium tert-butylate, or sodium
hydride, at temperatures between 0° C. and 100° C.

##STR00024##

[0162] Acid 5 can also be synthesized as outlined in scheme 6. In this
case A2 is O, S or SO2, R1, m and n are as defined above,
X is a leaving group such as bromine, iodine, or methanesulfonyloxy. The
alkylation of carboxylic acid 17 with halide or sulfonate 16 is performed
in an analogous fashion to that of 16 with 17 (scheme 5).

##STR00025##

[0163] Acid 5, in which A2 is N(R2), is represented as a
compound of formula 18. The compound of formula 18 can be synthesized as
outlined in scheme 7. R1, R2, m and n are as defined above.

##STR00026##

[0164] In step a, scheme 7, dicarboxylic acid monoester 19 is reduced to
ω-hydroxyester 20, using reagents known in the art, e.g.,
borane-tetrahydrofuran complex, in a solvent such as tetrahydrofuran, at
temperatures between 0° C. and 50° C.

[0165] In step b, scheme 7, the hydroxy group of 20 is oxidized to a
formyl group, leading to 21. Suitable reagents are e.g., sodium
hypochlorite, in the presence of potassium bromide,
2,2,6,6-tetramethylpiperidin-1-oxyl, and sodium hydrogencarbonate, in a
biphasic mixture of water and dichloromethane, at around 0° C.
Alternatively dimethyl sulfoxide-based reagents can be employed, such as
dimethyl sulfoxide-oxalyl chloride, or dimethyl sulfoxide-trifluoroacetic
anhydride, in a solvent such as dichloromethane, at temperatures below
0° C., typically at -78° C.

[0166] In step c, scheme 7, aldehyde 21 is reacted with amine 22 in the
presence of a reducing agent to give aminoester 23. Typically used
reagents are sodium borohydride (optionally in the presence of
titanium(IV)isopropoxide), sodium cyanoborohydride, or sodium
triacetoxyborohydride, in solvents such as methanol, acetic acid,
tetrahydrofuran, 1,2-dichloroethane, or mixtures thereof, at temperatures
between 0° C. and 100° C.

[0167] In step d, scheme 7, aminoester 23 is converted to acid 18 by
base-catalyzed hydrolysis, using reagents such as lithium hydroxide,
sodium hydroxide, potassium hydroxide, in solvents such as water,
methanol, ethanol, tetrahydrofuran, or mixtures thereof, at temperatures
between 0° C. and 100° C.

[0168] Alternatively, aminoester 23 can be accessed as outlined in scheme
8. R1, R2 and m are as defined above, Ra is lower alkyl,
e.g., methyl or ethyl.

##STR00027##

[0169] In step a, scheme 8, amide 24 is obtained from acid 19 by treatment
with amine 22, using reagents and methods as described for the reaction
of carboxylic acid 5 with amine 3.

[0170] In step b, scheme 8, aminoester 23 is obtained by reduction of
amide 24, using reagents such as diborane, borane-dimethylsulfide complex
or borane-tetrahydrofuran complex in solvents such as tetrahydrofuran at
temperatures between 0° C. and 100° C.

[0171] Unsaturated acids of general formula 6 can be synthesized as
outlined in scheme 9. R1 and m are as defined above, Ra is
lower alkyl, e.g., methyl or ethyl.

##STR00028##

[0172] In step a, scheme 9, unsaturated ester 25 is reacted with styrene
derivative 26 in an alkene cross-metathesis reaction, leading to 27. This
reaction is carried out in an inert solvent, such as dichloromethane or
toluene and requires a suitable catalyst, e.g.,
dichloro(1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)(phenylmethylene)(tr-
icyclohexyl-phosphine)ruthenium, at temperatures between 20° C. and
100° C.

[0174] Alternatively, unsaturated acids of formula 6 can be synthesized as
outlined in scheme 10. R1 and m are as defined above.

##STR00029##

[0175] In step a, scheme 10, ω-bromoacid 28 is reacted with
triphenylphosphine, leading to phosphonium salt 29. This reaction is
carried out in an inert solvent such as toluene, at temperatures between
20° C. and 110° C.

[0176] In step b, scheme 10, phosphonium salt 29 is reacted with aldehyde
30, leading to 6. This reaction is carried out in the presence of a base,
e.g., sodium hydride, n-butyllithium, or potassium tert-butylate, in a
solvent such as diethyl ether or tetrahydrofuran, at temperatures between
-20° C. and 50° C.

[0177] As described above, the novel compounds of formula I of the present
invention have been found to inhibit carnitine palmitoyl transferase 2
(CPT2) activity. The compounds of the present invention can therefore be
used in the treatment and/or prophylaxis of diseases that are modulated
by CPT2 inhibitors, particularly diseases that are related to
hyperglycemia and/or glucose tolerance disorders. Such diseases include
e.g. diabetes and associated pathologies, non insulin dependent diabetes
mellitus, obesity, hypertension, insulin resistance syndrome, metabolic
syndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,
atherosclerosis, congestive heart failure and renal failure.

[0178] The invention therefore also relates to pharmaceutical compositions
comprising a compound of formula I as defined above and a
pharmaceutically acceptable carrier and/or adjuvant.

[0180] In another preferred embodiment, the invention relates to a method
for the therapeutic and/or prophylactic treatment of diseases which are
modulated by CPT2 inhibitors, particularly for the therapeutic and/or
prophylactic treatment of hyperglycemia, glucose tolerance disorders,
diabetes and associated pathologies, non insulin dependent diabetes
mellitus, obesity, hypertension, insulin resistance syndrome, metabolic
syndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,
atherosclerosis, congestive heart failure and renal failure, which method
comprises administering a compound of formula I as defined above to a
human being or animal.

[0181] The invention also relates to the use of compounds of formula I as
described above for the preparation of medicaments for the therapeutic
and/or prophylactic treatment of diseases which are modulated by CPT2
inhibitors, particularly for the therapeutic and/or prophylactic
treatment of hyperglycemia, glucose tolerance disorders, diabetes and
associated pathologies, non insulin dependent diabetes mellitus, obesity,
hypertension, insulin resistance syndrome, metabolic syndrome,
hyperlipidemia, hypercholesterolemia, fatty liver disease,
atherosclerosis, congestive heart failure and renal failure. Such
medicaments comprise a compound of formula I as described above.

[0183] The following tests were carried out in order to determine the
activity of the compounds of the present invention. Background
information on the performed assays can be found in: Jackson et al.,
1999, Biochem. J. 341, 483-489 and Jackson et al., 2000, J. Biol. Chem.
275, 19560-19566.

[0184] Human and rat CPT2- and liver CPT1 cDNAs, and human muscle CPT1
cDNA were subcloned in pGAPZB or pGAPZA, respectively. These plasmids
were used to transform P. pastoris strain X-33 via electroporation after
the preparation of electrocompetent cells. High copy number clones were
selected where necessary using 0.5 or 1 mg/ml Zeocin. Cultures for
activity measurements were induced for 16 h in YPD medium (1% yeast
extract, 2% peptone, 2% glucose). Crude cell extracts were prepared by
disrupting the cells with glass beads or French Press, depending on
fermenter sizes. After centrifugation, the cell-free extracts were
resuspended in cell breaking buffer (50 mM Tris, pH7.4, 100 mM KCl, 1 mM
EDTA) in the presence of a protease inhibitor cocktail, before aliquoting
and freezing at -20° C.

[0185] CPT activity was measured using a spectrophotometric assay using
5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) also called Ellman's
reagent. The HS--CoA released on the formation of acylcarnitine from
carnitine (500 μM) and palmitoyl-CoA (80 μM) reduced DTNB (300
μM) forming 5-mercapto-2-nitrobenzoic acid which absorbed at 410 nm
with a molar extinction coefficient of 13600 M-1cm-1. The assay
buffer contained 120 mM KCl, 25 mM Tris, pH 7.4, 1 mM EDTA. This assay
was used for the identification of CPT inhibitors,
particularly/preferentially CPT2-selective inhibitors, versus the liver
and muscle CPT1 isoforms.

[0186] The compounds according to formula I preferably have an IC50
value (CPT2) below 10 μM, preferably 1 nM to 10 μM, more preferably
1 nM to 1 μM. The following table shows data for some examples.

[0187] The compounds of formula I and/or their pharmaceutically acceptable
salts can be used as medicaments, e.g. in the form of pharmaceutical
preparations for enteral, parenteral or topical administration. They can
be administered, for example, perorally, e.g. in the form of tablets,
coated tablets, dragees, hard and soft gelatine capsules, solutions,
emulsions or suspensions, rectally, e.g. in the form of suppositories,
parenterally, e.g. in the form of injection solutions or suspensions or
infusion solutions, or topically, e.g. in the form of ointments, creams
or oils. Oral administration is preferred.

[0188] The production of the pharmaceutical preparations can be effected
in a manner which will be familiar to any person skilled in the art by
bringing the described compounds of formula I and/or their
pharmaceutically acceptable salts, optionally in combination with other
therapeutically valuable substances, into a galenical administration form
together with suitable, non-toxic, inert, therapeutically compatible
solid or liquid carrier materials and, if desired, usual pharmaceutical
adjuvants.

[0191] The dosage of the compounds of formula I can vary within wide
limits depending on the disease to be controlled, the age and the
individual condition of the patient and the mode of administration, and
will, of course, be fitted to the individual requirements in each
particular case. For adult patients a daily dosage of about 1 to 2000 mg,
especially about 1 to 500 mg, comes into consideration. Depending on the
severity of the disease and the precise pharmacokinetic profile the
compound could be administered with one or several daily dosage units,
e.g. in 1 to 3 dosage units.

[0192] The pharmaceutical preparations conveniently contain about 1 to 500
mg, preferably 1 to 200 mg, of a compound of formula I.

[0193] The following examples serve to illustrate the present invention in
more detail. They are, however, not intended to limit its scope in any
manner.

[0205] The title compound, m/e=413.3 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 2,5-difluorobenzyl bromide, leading to
8-(2,5-difluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(2,5-difluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(2,5-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino--
butyric acid benzyl ester, which was hydrogenated in step 4.

[0206] The title compound, m/e=413.1 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 2,4-difluorobenzyl bromide, leading to
8-(2,4-difluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(2,4-difluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(2,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino--
butyric acid benzyl ester, which was hydrogenated in step 4.

[0207] The title compound, m/e=432.5 ([M+H].sup.+), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 2,3,4-trifluorobenzyl bromide, leading to
8-(2,3,4-trifluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(2,3,4-trifluoro-benzyloxy)-octanoic acid. This was coupled in step 3
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride to produce
(R)-3-[8-(2,3,4-trifluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyr-
ic acid benzyl ester, which was hydrogenated in step 4.

[0208] The title compound, m/e=467.5 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with pentafluorobenzyl bromide, leading to
8-(pentafluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(pentafluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(pentafluoro-benzyloxy)-octanoylamino]-4-dimethylamino-b-
utyric acid benzyl ester, which was hydrogenated in step 4.

[0209] The title compound, m/e=445.6 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 4-trifluoromethyl-benzyl bromide, leading to
8-(4-trifluoromethyl-benzyloxy)-octan-1-ol, which was oxidized in step 2
to 8-(4-trifluoromethyl-benzyloxy)-octanoic acid. This was coupled in
step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride to produce
(R)-3-[8-(4-trifluoromethyl-benzyloxy)-octanoylamino]-4-dimethylamino-but-
yric acid benzyl ester, which was hydrogenated in step 4.

[0210] The title compound, m/e=463.5 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 3-fluoro-4-trifluoromethyl-benzyl bromide, leading to
8-(3-fluoro-4-trifluoromethyl-benzyloxy)-octan-1-ol, which was oxidized
in step 2 to 8-(3-fluoro-4-trifluoromethyl-benzyloxy)-octanoic acid. This
was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid
benzyl ester dihydrochloride to produce
(R)-3-[8-(3-fluoro-4-trifluoromethyl-benzyloxy)-octanoylamino]-4-dimethyl-
amino-butyric acid benzyl ester, which was hydrogenated in step 4.

[0211] The title compound, m/e=407.6 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 4-methoxy-benzyl bromide, leading to
8-(4-methoxy-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(4-methoxy-benzyloxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(4-methoxy-benzyloxy)-octanoylamino]-4-dimethylamino-but-
yric acid benzyl ester, which was hydrogenated in step 4.

[0212] The title compound, m/e=455.3 ([M+H].sup.+), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 4-(bromomethyl)-biphenyl, leading to
8-(biphenyl-4-ylmethoxy)-octan-1-ol, which was oxidized in step 2 to
8-(biphenyl-4-ylmethoxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(biphenyl-4-ylmethoxy)-octanoylamino]-4-dimethylamino-bu-
tyric acid benzyl ester, which was hydrogenated in step 4.

[0213] The title compound, m/e=463.1 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 2-fluoro-4-trifluoromethyl-benzyl bromide, leading to
8-(2-fluoro-4-trifluoromethyl-benzyloxy)-octan-1-ol, which was oxidized
in step 2 to 8-(2-fluoro-4-trifluoromethyl-benzyloxy)-octanoic acid. This
was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid
benzyl ester dihydrochloride to produce
(R)-3-[8-(2-fluoro-4-trifluoromethyl-benzyloxy)-octanoylamino]-4-dimethyl-
amino-butyric acid benzyl ester, which was hydrogenated in step 4.

[0214] The title compound, m/e=479.4 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 2,3,5,6-tetrafluoro-4-methoxy-benzyl bromide, leading to
8-(2,3,5,6-tetrafluoro-4-methoxy-benzyloxy)-octan-1-ol, which was
oxidized in step 2 to
8-(2,3,5,6-tetrafluoro-4-methoxy-benzyloxy)-octanoic acid. This was
coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl
ester dihydrochloride to produce
(R)-3-[8-(2,3,5,6-tetrafluoro-4-methoxy-benzyloxy)-octanoylamino]-4-dimet-
hylamino-butyric acid benzyl ester, which was hydrogenated in step 4.

[0215] The title compound, m/e=427.1 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 1-bromomethyl-naphthalene, leading to
8-(naphthalen-1-ylmethoxy)-octan-1-ol, which was oxidized in step 2 to
8-(naphthalen-1-ylmethoxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(naphthalen-1-ylmethoxy)-octanoylamino]-4-dimethylamino--
butyric acid benzyl ester, which was hydrogenated in step 4.

[0216] The title compound, m/e=397.4 ([M+H].sup.+), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 2-fluorobenzyl bromide, leading to
8-(2-fluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(2-fluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(2-fluoro-benzyloxy)-octanoylamino]-4-dimethylamino-buty-
ric acid benzyl ester, which was hydrogenated in step 4.

[0217] The title compound, m/e=397.4 ([M+H].sup.+), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with 3-fluorobenzyl bromide, leading to
8-(3-fluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(3-fluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(3-fluoro-benzyloxy)-octanoylamino]-4-dimethylamino-buty-
ric acid benzyl ester, which was hydrogenated in step 4.

[0218] The title compound, m/e=397.4 ([M+H].sup.+), was produced in
analogy with example 1, steps 1-4. Thus, 1,8-octanediol was alkylated in
step 1 with 4-fluorobenzyl bromide, leading to
8-(4-fluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(4-fluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(4-fluoro-benzyloxy)-octanoylamino]-4-dimethylamino-buty-
ric acid benzyl ester, which was hydrogenated in step 4.

[0219] The title compound, m/e=415.5 ([M+H].sup.+), was produced in
analogy with example 1, steps 1-4. Thus, 1,8-octanediol was alkylated in
step 1 with 2,3-difluorobenzyl bromide, leading to
8-(2,3-difluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to
8-(2,3-difluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-[8-(2,3-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino--
butyric acid benzyl ester, which was hydrogenated in step 4.

Example 17

(R)-3-(8-Benzyloxy-octanoylamino)-4-dimethylamino-butyric acid

[0220] The title compound, m/e=377.6 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated
in step 1 with benzyl bromide, leading to 8-benzyloxy-octan-1-ol, which
was oxidized in step 2 to 8-benzyloxy-octanoic acid. This was coupled in
step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride to produce
(R)-3-[8-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl
ester, which was hydrogenated in step 4.

[0222] Potassium carbonate (2.59 g, 18.7 mmol) and 9-bromo-1-nonanol (1.39
g, 6.24 mmol) were added at room temperature to a solution of
2-fluorophenol (700 mg, 6.24 mmol) in N,N-dimethylformamide (20 mL), then
after 40 h insoluble material was removed by filtration. The filtrate was
evaporated and the residue taken up in dichloromethane, washed with 1 M
aq. sodium hydroxide solution, dried over sodium sulfate, filtered, and
evaporated, to afford 9-(2-fluoro-phenoxy)-nonan-1-ol (1.7 g), which was
directly used in the next step.

[0229] The title compound, m/e=397.4 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, 3-fluorophenol was alkylated
in step 1 with 9-bromo-1-nonanol, leading to
9-(3-fluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(3-fluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(3-fluoro-phenoxy)-nonanoylamino]-butyri-
c acid benzyl ester, which was hydrogenated in step 4.

[0230] The title compound, m/e=395.5 ([M-H].sup.-), was produced in
analogy with example 18, steps 1 to 4. Thus, 4-fluorophenol was alkylated
in step 1 with 9-bromo-1-nonanol, leading to
9-(4-fluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(4-fluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(4-fluoro-phenoxy)-nonanoylamino]-butyri-
c acid benzyl ester, which was hydrogenated in step 4.

[0231] The title compound, m/e=415.5 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, 2,3-difluorophenol was
alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-(2,3-difluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(2,3-difluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(2,3-difluoro-phenoxy)-nonanoylamino]-bu-
tyric acid benzyl ester, which was hydrogenated in step 4.

[0232] The title compound, m/e=413.6 ([M-H].sup.-), was produced in
analogy with example 18, steps 1 to 4. Thus, 2,4-difluorophenol was
alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-(2,4-difluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(2,4-difluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(2,4-difluoro-phenoxy)-nonanoylamino]-bu-
tyric acid benzyl ester, which was hydrogenated in step 4.

[0233] The title compound, m/e=413.6 ([M-H].sup.-), was produced in
analogy with example 18, steps 1 to 4. Thus, 3,4-difluorophenol was
alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-(3,4-difluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(3,4-difluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(3,4-difluoro-phenoxy)-nonanoylamino]-bu-
tyric acid benzyl ester, which was hydrogenated in step 4.

[0234] The title compound, m/e=433.5 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, 2,3,4-trifluorophenol was
alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-(2,3,4-trifluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(2,3,4-trifluoro-phenoxy)-nonanoic acid. This was coupled in step 3
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride to produce
(R)-4-dimethylamino-3-[9-(2,3,4-trifluoro-phenoxy)-nonanoylamino]-butyric
acid benzyl ester, which was hydrogenated in step 4.

[0235] The title compound, m/e=455.3 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, biphenyl-4-ol was alkylated
in step 1 with 9-bromo-1-nonanol, leading to
9-(biphenyl-4-yloxy)-nonan-1-ol, which was oxidized in step 2 to
9-(biphenyl-4-yloxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(biphenyl-4-yloxy)-nonanoylamino]-butyri-
c acid benzyl ester, which was hydrogenated in step 4.

[0236] The title compound, m/e=439.4 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, 3,4-dimethoxyphenol was
alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-(3,4-dimethoxy-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(3,4-dimethoxy-phenoxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(3,4-dimethoxy-phenoxy)-nonanoylamino]-b-
utyric acid benzyl ester, which was hydrogenated in step 4.

[0237] The title compound, m/e=447.4 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, 4-trifluoromethyl-phenol was
alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-(4-trifluoromethyl-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(4-trifluoromethyl-phenoxy)-nonanoic acid. This was coupled in step 3
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride to produce
(R)-4-dimethylamino-3-[9-(4-trifluoromethyl-phenoxy)-nonanoylamino]-butyr-
ic acid benzyl ester, which was hydrogenated in step 4.

[0238] The title compound, m/e=409.5 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, 4-methoxy-phenol was
alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-(4-methoxy-phenoxy)-nonan-1-ol, which was oxidized in step 2 to
9-(4-methoxy-phenoxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(4-methoxy-phenoxy)-nonanoylamino]-butyr-
ic acid benzyl ester, which was hydrogenated in step 4.

[0239] The title compound, m/e=429.5 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, naphthalen-1-ol was
alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-(naphthalen-1-yloxy)-nonan-1-ol, which was oxidized in step 2 to
9-(naphthalen-1-yloxy)-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[9-(naphthalen-1-yloxy)-nonanoylamino]-buty-
ric acid benzyl ester, which was hydrogenated in step 4.

Example 30

(R)-4-Dimethylamino-3-(11-phenoxy-undecanoylamino)-butyric acid

[0240] The title compound, m/e=405.7 ([M-H].sup.-), was produced in
analogy with example 18, steps 1 to 4. Thus, phenol was alkylated in step
1 with 11-bromo-1-undecanol, leading to 11-phenoxy-undecan-1-ol, which
was oxidized in step 2 to 11-phenoxy-undecanoic acid. This was coupled in
step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride to produce
(R)-4-dimethylamino-3-[1'-phenoxy-undecanoylamino]-butyric acid benzyl
ester, which was hydrogenated in step 4.

Example 31

(R)-4-Dimethylamino-3-(9-phenoxy-nonanoylamino)-butyric acid

[0241] The title compound, m/e=379.4 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, phenol was alkylated in step
1 with 9-bromo-1-nonanol, leading to 9-phenoxy-nonan-1-ol, which was
oxidized in step 2 to 9-phenoxy-nonanoic acid. This was coupled in step 3
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride to produce
(R)-4-dimethylamino-3-[9-phenoxy-nonanoylamino]-butyric acid benzyl
ester, which was hydrogenated in step 4.

Example 32

(R)-4-Dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid

[0242] The title compound, m/e=377.3 ([M+H].sup.+), was produced in
analogy with example 1, steps 3 and 4. Thus, commercially available
10-phenyldecanoic acid was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid
benzyl ester, which was hydrogenated in step 4.

Example 33

(S)-4-Dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid

[0243] The title compound, m/e=377.5 ([M+H].sup.+), was produced in
analogy with example 1, steps 3 and 4. Thus, commercially available
10-phenyldecanoic acid was coupled in step 3 with
(S)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (S)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid
benzyl ester, which was hydrogenated in step 4.

[0247] To a solution of 9-bromo-nonanoic acid (7.00 g, 29.5 mmol) in
toluene (10 mL) was added triphenylphosphine (7.74 g, 29.5 mmol). The
solution was sealed under nitrogen in a pressure tube and heated at
110° C. for 18 hours. On reaction completion two phases were
observed. The toluene top layer was decanted from the crude product which
was washed with toluene. (8-Carboxy-octyl)-triphenyl-phosphonium bromide
(14.9 g) was obtained, which was directly used in the next step. White
semisolid, m/e=419.3 ([M+H].sup.+).

[0262] The title compound, m/e=405.4 ([M+H].sup.+), was produced in
analogy with example 35, steps 1 to 4. Thus, 9-decenoic acid ethyl ester
was reacted in step 1 with 2,5-dimethylstyrene, leading to
10-(2,5-dimethyl-phenyl)-dec-9-enoic acid ethyl ester, which was
hydrolyzed in step 2 to 10-(2,5-dimethyl-phenyl)-dec-9-enoic acid. In
step 3, this was converted to 10-(2,5-dimethyl-phenyl)-dec-9-enoyl
chloride, then reacted with (R)-3-amino-4-dimethylamino-butyric acid
benzyl ester dihydrochloride, leading to
(R)-4-dimethylamino-3-[10-(2,5-dimethyl-phenyl)-dec-9-enoylamino]-butyric
acid benzyl ester, which was hydrogenated in step 4.

[0263] The title compound, m/e=405.3 ([M+H].sup.+), was produced in
analogy with example 34, steps 2 to 4. Thus 2,6-dimethylbenzaldehyde was
reacted in step 2 with (8-carboxy-octyl)-triphenyl-phosphonium bromide,
leading to 10-(2,6-dimethyl-phenyl)-dec-9-enoic acid. In step 3, this was
converted to 10-(2,6-dimethyl-phenyl)-dec-9-enoyl chloride, then reacted
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride, leading to
(R)-4-dimethylamino-3-[10-(2,6-dimethyl-phenyl)-dec-9-enoylamino]-butyric
acid benzyl ester, which was hydrogenated in step 4.

[0264] The title compound, m/e=407.3 ([M+H].sup.+), was produced in
analogy with example 35, steps 1 to 4. Thus, 9-decenoic acid ethyl ester
was reacted in step 1 with 4-methoxystyrene, leading to
10-(4-methoxy-phenyl)-dec-9-enoic acid ethyl ester, which was hydrolyzed
in step 2 to 10-(4-methoxy-phenyl)-dec-9-enoic acid. In step 3, this was
converted to 10-(4-methoxy-phenyl)-dec-9-enoyl chloride, then reacted
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride, leading to
(R)-4-dimethylamino-3-[10-(4-methoxy-phenyl)-dec-9-enoylamino]-butyric
acid benzyl ester, which was hydrogenated in step 4.

Example 39

(R)-4-Dimethylamino-3-(10-naphthalen-1-yl-decanoylamino)-butyric acid

[0265] The title compound, m/e=427.4 ([M+H].sup.+), was produced in
analogy with example 35, steps 1 to 4. Thus, 9-decenoic acid ethyl ester
was reacted in step 1 with 1-vinylnaphthalene, leading to
10-(naphthalene-1-yl)-dec-9-enoic acid ethyl ester, which was hydrolyzed
in step 2 to 10-(naphthalene-1-yl)-dec-9-enoic acid. In step 3, this was
converted to 10-(naphthalene-1-yl)-dec-9-enoyl chloride, then reacted
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride, leading to
(R)-4-dimethylamino-3-[10-(naphthalene-1-yl)-dec-9-enoylamino]-butyric
acid benzyl ester, which was hydrogenated in step 4.

[0266] The title compound, m/e=445.1 ([M+H].sup.+), was produced in
analogy with example 35, steps 1 to 4. Thus, 9-decenoic acid ethyl ester
was reacted in step 1 with 4-trifluoromethylstyrene, leading to
10-(4-trifluoromethyl-phenyl)-dec-9-enoic acid ethyl ester, which was
hydrolyzed in step 2 to 10-(4-trifluoromethyl-phenyl)-dec-9-enoic acid.
In step 3, this was converted to 1044-trifluoromethyl-phenyl)-dec-9-enoyl
chloride, then reacted with (R)-3-amino-4-dimethylamino-butyric acid
benzyl ester dihydrochloride, leading to
(R)-4-dimethylamino-3-[10-(4-trifluoromethyl-phenyl)-dec-9-enoylamino]-bu-
tyric acid benzyl ester, which was hydrogenated in step 4.

[0267] The title compound, m/e=395.3 ([M+H].sup.+), was produced in
analogy with example 35, steps 1 to 4. Thus, 9-decenoic acid ethyl ester
was reacted in step 1 with 3-fluorostyrene, leading to
10-(3-fluoro-phenyl)-dec-9-enoic acid ethyl ester, which was hydrolyzed
in step 2 to 1043-fluoro-phenyl)-dec-9-enoic acid. In step 3, this was
converted to 10-(3-fluoro-phenyl)-dec-9-enoyl chloride, then reacted with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride,
leading to
(R)-4-dimethylamino-3-[10-(3-fluoro-phenyl)-dec-9-enoylamino]-butyric
acid benzyl ester, which was hydrogenated in step 4.

[0268] The title compound, m/e=413.3 ([M+H].sup.+), was produced in
analogy with example 34, steps 2 to 4. Thus 2,3-difluorobenzaldehyde was
reacted in step 2 with (8-carboxy-octyl)-triphenyl-phosphonium bromide,
leading to 10-(2,3-difluoro-phenyl)-dec-9-enoic acid. In step 3, this was
converted to 10-(2,3-difluoro-phenyl)-dec-9-enoyl chloride, then reacted
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride, leading to
(R)-4-dimethylamino-3-[10-(2,3-difluoro-phenyl)-dec-9-enoylamino]-butyric
acid benzyl ester, which was hydrogenated in step 4.

[0277] The title compound, m/e=384.3 ([M+H].sup.+), was produced in
analogy with example 43, steps 1 to 4. Thus, thiazole-5-carboxaldehyde
was reacted in step 1 with (8-carboxy-octyl)-triphenyl-phosphonium
bromide, leading to 10-(thiazol-5-yl)-dec-9-enoic acid. In step 2, this
was converted to 10-(thiazol-5-yl)-dec-9-enoyl chloride, then reacted
with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride, leading to
(R)-4-dimethylamino-3-[10-(2,3-difluoro-phenyl)-dec-9-enoylamino]-butyric
acid benzyl ester. In step 3, reaction of
(R)-4-dimethylamino-3-[10-(2,3-difluoro-phenyl)-dec-9-enoylamino]-butyric
acid benzyl ester with triethylsilane-trifluoroacetic acid produced
4-dimethylamino-3-(10-thiazol-5-yl-decanoylamino)-butyric acid benzyl
ester, which was hydrolyzed in step 4.

Example 45

(R)-4-Dimethylamino-3-(6-phenyl-hexanoylamino)-butyric acid

[0278] The title compound, m/e=321.3 ([M+H].sup.+), was produced in
analogy with example 1, steps 3 and 4. Thus, commercially available
6-phenylhexanoic acid was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-(6-phenyl-hexanoylamino)-butyric acid
benzyl ester, which was hydrogenated in step 4.

Example 46

(R)-4-Dimethylamino-3-(7-phenyl-heptanoylamino)-butyric acid

[0279] The title compound, m/e=335.4 ([M+H].sup.+), was produced in
analogy with example 1, steps 3 and 4. Thus, commercially available
7-phenylheptanoic acid was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-(7-phenyl-heptanoylamino)-butyric acid
benzyl ester, which was hydrogenated in step 4.

Example 47

(R)-4-Dimethylamino-3-(8-phenyl-octanoylamino)-butyric acid

[0280] The title compound, m/e=347.4 ([M-H].sup.-), was produced in
analogy with example 1, steps 3 and 4. Thus, commercially available
8-phenyloctanoic acid was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-(8-phenyl-octanoylamino)-butyric acid
benzyl ester, which was hydrogenated in step 4.

Example 48

(R)-4-Dimethylamino-3-(9-phenyl-nonanoylamino)-butyric acid

[0281] The title compound, m/e=361.5 ([M-H].sup.-), was produced in
analogy with example 1, steps 3 and 4. Thus, commercially available
9-phenylnonanoic acid was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-(9-phenyl-nonanoylamino)-butyric acid
benzyl ester, which was hydrogenated in step 4.

[0283] The title compound, m/e=391.5 ([M+H].sup.+), was produced in
analogy with example 1, steps 3 and 4. Thus, commercially available
11-phenylundecanoic acid was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-(11-phenyl-undecanoylamino)-butyric acid
benzyl ester, which was hydrogenated in step 4.

Example 51

(R)-4-Dimethylamino-3-(12-phenyl-dodecanoylamino)-butyric acid

[0284] The title compound, m/e=403.6 ([M-H].sup.-), was produced in
analogy with example 1, steps 3 and 4. Thus, commercially available
12-phenyldodecanoic acid was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-(12-phenyl-dodecanoylamino)-butyric acid
benzyl ester, which was hydrogenated in step 4.

[0291] The title compound, m/e=379.4 ([M+H].sup.+) was produced in analogy
with example 1, steps 1 to 4. Thus, 1,6-hexanediol was alkylated in step
1 with 1-bromo-3-phenylpropane, leading to
6-(3-phenyl-propoxy)-hexan-1-ol, which was oxidized in step 2 to
6-(3-phenyl-propoxy)-hexanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-4-dimethylamino-3-[6-(3-phenyl-propoxy)-hexanoylamino]-butyri-
c acid benzyl ester, which was hydrogenated in step 4.

[0304] The title compound, m/e=405.7 ([M-H].sup.-), was produced in
analogy with example 54, steps 1 to 6. Thus, 8-bromo-1-octanol was
protected in step 1, leading to 2-(8-bromo-octyloxy)-tetrahydro-pyran,
which was reacted in step 2 with 3-phenoxypropanol, affording
2-(8-(3-phenyl-propoxy)-octyloxy)-tetrahydro-pyran, which after
deprotection in step 3 gave 8-(3-phenyl-propoxy)-octan-1-ol. This was
oxidized in step 4 to 8-(3-phenyl-propoxy)-octanoic acid, which was
coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl
ester dihydrochloride, leading to
(R)-4-dimethylamino-3-[8-(3-phenyl-propoxy)-octanoylamino]-butyric acid
benzyl ester, which was hydrogenated in step 6.

[0305] The title compound, m/e=407.6 ([M-H].sup.-), was produced in
analogy with example 54, steps 1 to 6. Thus, 8-bromo-1-octanol was
protected in step 1, leading to 2-(8-bromo-octyloxy)-tetrahydro-pyran,
which was reacted in step 2 with 2-phenoxyethanol, affording
2-(8-(2-phenoxy-ethoxy)-octyloxy)-tetrahydro-pyran, which after
deprotection in step 3 gave 8-(2-phenoxy-ethoxy)-octan-1-ol. This was
oxidized in step 4 to 8-(2-phenoxy-ethoxy)-octanoic acid, which was
coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl
ester dihydrochloride, leading to
(R)-4-dimethylamino-3-[8-(2-phenoxy-ethoxy)-octanoylamino]-butyric acid
benzyl ester, which was hydrogenated in step 6.

Example 57

(R)-3-(10-Benzyloxy-decanoylamino)-4-dimethylamino-butyric acid

[0306] The title compound, m/e=405.6 ([M-H].sup.-), was produced in
analogy with example 1, steps 1 to 4. Thus, 1,10-decanediol was alkylated
in step 1 with benzyl bromide, leading to 10-benzyloxy-decan-1-ol, which
was oxidized in step 2 to 10-benzyloxydecanoic acid. This was coupled in
step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride to produce
(R)-3-(10-benzyloxy-decanoylamino)-4-dimethylamino-butyric acid benzyl
ester, which was hydrogenated in step 4.

[0310] Oxone® (3.3 g, 5.5 mmol) was added to a solution of
7-phenethylsulfanyl-heptan-1-ol (930 mg, 3.68 mmol) in methanol (40 mL),
then after 16 h insoluble material was removed by filtration and the
filtrate evaporated, affording 7-(2-phenyl-ethanesulfonyl)-heptan-1-ol
(1.6 g), which was directly used in the next step.

[0317] The title compound, m/e=427.4 ([M+H].sup.+) was produced in analogy
with example 59, steps 1 to 5. Thus, phenyl-methanethiol was alkylated in
step 1 with 8-bromo-1-octanol, leading to 8-benzylsulfanyl-octan-1-ol,
which was oxidized in step 2 to 8-phenylmethanesulfonyl-octan-1-ol. This
was oxidized in step 3 to 8-phenylmethanesulfonyl-octanoic acid, then
coupled in step 4 with (R)-3-amino-4-dimethylamino-butyric acid benzyl
ester dihydrochloride to produce
(R)-4-dimethylamino-3-(8-(phenylmethanesulfonyl)-octanoylamino)-butyric
acid benzyl ester, which was hydrogenated in step 5.

Example 60

(R)-3-(9-Benzenesulfonyl-nonanoylamino)-4-dimethylamino-butyric acid

[0318] The title compound, m/e=427.5 ([M+H].sup.+), was produced in
analogy with example 18, steps 1 to 4. Thus, benzenesulfinic acid sodium
salt was alkylated in step 1 with 9-bromo-1-nonanol, leading to
9-benzenesulfonyl-nonan-1-ol, which was oxidized in step 2 to
9-benzenesulfonyl-nonanoic acid. This was coupled in step 3 with
(R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to
produce (R)-3-(9-benzenesulfonyl-nonanoylamino)-4-dimethylamino-butyric
acid benzyl ester, which was hydrogenated in step 4.

[0319] The title compound, m/e=413.5 ([M-H].sup.-), was produced in
analogy with example 54, steps 1 to 6. Thus, 7-bromo-1-heptanol was
protected in step 1, leading to 2-(7-bromo-heptyloxy)-tetrahydro-pyran,
which was reacted in step 2 with 2-(2,3-difluorophenoxy)-ethanol,
affording 2-(7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptyloxy)-tetrahydro-pyr-
an, which after deprotection in step 3 gave
7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptan-1-ol. This was oxidized in step
4 to 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoic acid, which was coupled
in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride, leading to
(R)-3-{7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoylamino}-4-dimethylamino-
-butyric acid benzyl ester, which was hydrogenated in step 6.

[0326] The title compound, m/e=392.4 ([M+H].sup.+), was produced in
analogy with example 62, steps 1 to 3. Thus 10-phenyldecanoic acid was
elaborated in step 1 to 9-phenyl-nonyl-isocyanate. This was coupled in
step 2 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester
dihydrochloride, leading to
(R)-4-dimethylamino-3-[3-(9-phenyl-nonyl)-ureido]-butyric acid benzyl
ester, which was hydrogenated in step 3.

[0335] The title compound, m/e=406.6 ([M+H].sup.+), was produced in
analogy with example 64, steps 1 to 4. Thus, 9-oxononanoic acid methyl
ester was reacted in step 1 with N-benzyl-2-phenylethylamine, leading to
9-(benzyl-phenethyl-amino)-nonanoic acid methyl ester, which was
hydrolyzed in step 2 to afford 9-(benzyl-phenethyl-amino)-nonanoic acid.
This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid
benzyl ester dihydrochloride, leading to
(R)-3-[9-(benzyl-phenethyl-amino)-nonanoylamino]-4-dimethylamino-butyric
acid benzyl ester, which was hydrogenated in step 4.

[0347] The active ingredient is sieved and mixed with microcrystalline
cellulose and the mixture is granulated with a solution of
polyvinylpyrrolidon in water. The granulate is mixed with sodium starch
glycolate and magesiumstearate and compressed to yield kernels of 120 or
350 mg respectively. The kernels are lacquered with an aqueous
solution/suspension of the above mentioned film coat.

Example B

[0348] Capsules containing the following ingredients can be manufactured
in a conventional manner:

[0351] The active ingredient is dissolved in a mixture of polyethylene
glycol 400 and water for injection (part). The pH is adjusted to 5.0 with
acetic acid. The volume is adjusted to 1.0 ml by addition of the residual
amount of water. The solution is filtered, filled into vials using an
appropriate overage and sterilized.

Example D

[0352] Soft gelatin capsules containing the following ingredients can be
manufactured in a conventional manner:

[0353] The active ingredient is dissolved in a warm melting of the other
ingredients and the mixture is filled into soft gelatin capsules of
appropriate size. The filled soft gelatin capsules are treated according
to the usual procedures.

Example E

[0354] Sachets containing the following ingredients can be manufactured in
a conventional manner:

[0355] The active ingredient is mixed with lactose, microcrystalline
cellulose and sodium carboxymethyl cellulose and granulated with a
mixture of polyvinylpyrrolidone in water. The granulate is mixed with
magnesiumstearate and the flavoring additives and filled into sachets.